EP0450065A1 - Agent antiviral - Google Patents

Agent antiviral Download PDF

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Publication number
EP0450065A1
EP0450065A1 EP89900652A EP89900652A EP0450065A1 EP 0450065 A1 EP0450065 A1 EP 0450065A1 EP 89900652 A EP89900652 A EP 89900652A EP 89900652 A EP89900652 A EP 89900652A EP 0450065 A1 EP0450065 A1 EP 0450065A1
Authority
EP
European Patent Office
Prior art keywords
ammonium
compound
antiviral agent
concentration
antiviral
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP89900652A
Other languages
German (de)
English (en)
Other versions
EP0450065A4 (en
Inventor
Haruhisa 11-8 2-Chome Fujita
Toshihiro 13-905 4-Chome Yamase
Kouji 23-5-3 2-Chome Fukushima
Yoshiko 2-3-406 1-Chome Seto
Mariko 4-7 5-Chome Fukuma
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fukushima Kouji
Seto Yoshiko
Yamase Toshihiro
Terumo Corp
Original Assignee
Fukushima Kouji
Seto Yoshiko
Yamase Toshihiro
Terumo Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fukushima Kouji, Seto Yoshiko, Yamase Toshihiro, Terumo Corp filed Critical Fukushima Kouji
Publication of EP0450065A1 publication Critical patent/EP0450065A1/fr
Publication of EP0450065A4 publication Critical patent/EP0450065A4/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients

Definitions

  • This invention relates to an antiviral agent, particularly an agent to make herpesvirus ineffective, which exhibits an antiviral activity and possesses as an active component thereof a medicinally useful heteropolyoxymetalate.
  • a desire has been expressed to develop a highly satisfactory antiviral agent useful for combating the herpesviruses. It has been held heretofore that not less than 90% of the cases of HSV infection excepting the cases involving infants turn out to be unapparent in type.
  • the ACV nevertheless has a problem.
  • This problem contains the fact that the ACV, in spite of a conspicuous activity thereof manifested in resisting the HSV, incurs relatively early appearance of a resistant virus. This seems to be a phenomenon common to the ACV and other compounds similar to the component bases of nucleic acids possessing a HSV-resisting activity.
  • the manifestation of this activity comprises phosphorylation of the ACV into acyclo-GMP through the agency of thymidine kinase [TK(v)] capable of being induced by herpesvirus into infectious cells, transformation of the acyclo-GMP into acyclo-GTP through the agency of cellular thymidine kinase [TK(c)], conspicuous inhibition of the activity of a DNA-synthesizing enzyme by the acyclo-GTP, incorporation of the acyclo-GTP in the terminal of a DNA chain in process of synthesis and consequent formation of an end point of the DNA chain, and ensuant termination of the DNA synthesis.
  • TK(v) thymidine kinase
  • TK(c) cellular thymidine kinase
  • the ACV Since the ACV possesses more than 200 times as high affinity for TK(v) as for TK(c), it is phosphorylated much more quickly and more copiously in HSV-infected cells than in uninfected cells. This fact accounts for the high selective toxicity or the specific anti-herpes activity and, in the meantime, induces the appearance of a resistant virus. Viruses which are abnormal to TK or a DNA polymerase exhibit resistance to the ACV. Among the fundamental and clinical findings made to date are counted reports purporting to demonstrate the presence of HSV strain lacking TK in the clinically separated virus strains. The ACV does not act upon these virus strains. The following reports have been published to date concerning the antiviral activity of polyoxymetalate ion compounds.
  • the medicine (ACV) which is effective against the anti-herpes infectious disease as described above has been developed and put to practical use. Since this anti-herpes agent has relatively low toxicity (adverse side effect), it may well be said that the medicine has realized in a measure the therapy of the acute infectious disease of herpesvirus.
  • the ACV has such unsolved problems as the aforementioned appearance of a resistant virus and the lack of effectiveness against the TK virus.
  • the final objective of the control of the infectious disease caused by the herpesvirus resides in preventing the infection itself and extirpating the virus.
  • an antiviral agent having as an active component thereof a salt of a heteropoly-anion represented by the following general formula I: [XM12O40] p- (I) wherein X is an ion of at least one element selected from the group consisting of the transition metals of Groups III to VI in the Periodic Table of Elements, M is one member or a mixture of up to three members selected from the group consisting of the ions severally of molybdenum, tungsten, aluminum, vanadium, niobium, tantalum, cobalt, nickel, and titanium, O is oxygen atom, and P is a positive integer.
  • X is an ion of at least one element selected from the group consisting of the transition metals of Groups III to VI in the Periodic Table of Elements
  • M is one member or a mixture of up to three members selected from the group consisting of the ions severally of molybdenum, tungsten, aluminum, vanadium, niobium, tantalum, cobal
  • the antiviral agent of this invention prepared in the form of an aqueous solution is sufficiently stable chemically when the pH value thereof is in the range of from 4 to 8.
  • the sufficient chemical stability indicates that the time-course change of the aqueous solution of the polyoxometalate at room temperature is virtually nil because this change is determined by measuring the electric current which reflects an electrochemical reduction of the polyoxometalate ion.
  • this determination is carried out by preparing aqueous solutions of 0.1 M polyoxometalate adjusted pH 4 to 8 (with HClO4, HCl, and other buffer solutions) and subjecting these aqueous solutions to derivative pulse polarography with a dropping-mercury electrode (using a EG&G PRA-174A + 303 polarographic meter). A sample in which the peak value of electric current measured as described above at 2.5°C is retained above 70% over a period of one hour following the start of the test is reported as possessing sufficient chemical stability.
  • Pentapotassium dodecatungsto borate and heptapotassium dititanate decatungsto phosphate which are used in the antiviral agent (particularly the agent effective against herpesvirus) of this invention are salts of Keggin type heteropolyanions represented by the general formula, [XM12O40] p-, wherein X is one member or a mixture of up to three members selected from the group consisting of the ions severally of molybdenum, tungsten, aluminum, vanadium, niobium, tantalum, cobalt, nickel, and titanium, O is oxygen atom, and P is positive integer).
  • the polyoxotungstates to be used in this invention are oxo acid ion polycyclic complexes of a structure such that heteropolyoxometalates of a kind which are cluster compounds are joined through the medium of edges or apexes as basic unit structures generally having four or six oxygen atoms attached to a tungsten atom.
  • the polyoxometalate ions in these heteropolyoxometalate have the following general characteristic features.
  • polyoxometalate ions have the nature of effecting a photoredox reaction in a solid or a solution and, therefore, are confidently expected to find commercial utility in applications as to display function devices. Owing to their high reactivity, these compounds are estimated to possess a physiological activity.
  • polyoxometalate ions such as, for example, polyoxotungstates, possess a highly conspicuous antiviral effect (particularly against herpesvirus). They are expected to manifest effectiveness especially against various diseases caused by human retrovirus represented by the acquired immunological deficiency syndrome (AIDS) virus which has been raising a serious social issue. This expectation logically issues from the fact that the polyoxotungstates possess an activity of inhibiting the reverse transcriptase of the virus.
  • AIDS acquired immunological deficiency syndrome
  • the polyoxotungstates answering the description include the salts of cations severally of sodium, potassium, cesium, calcium, strontium, barium, ammonium, hydrogen, methyl ammonium, ethyl ammonium, dimethyl ammonium, trimethyl ammonium, tetramethyl ammonium, diethyl ammonium, isopropyl ammonium, diisopropyl ammonium, propyl ammonium, dipropyl ammonium, butyl ammonium, dibutyl ammonium, tributyl ammonium, tetrabutyl ammonium, and guanidinium, for example.
  • heteropolyoxometalate salts of this invention include the following compounds, as follows:
  • the antiviral agent (particularly against herpesvirus) of this invention generally contains in a solid carrier or a liquid carrier, preferably a liquid carrier, at least one of the aforementioned compounds of the general formula [XM12O40] p- .
  • the compounds conforming to this invention can be used in combination with known active substances.
  • the antiviral agent of this invention may be administered in any suitable and/or conventional mode.
  • the carrier for the compound is an aseptic liquid such as distilled water or physiological saline solution, particularly water.
  • the water carrier of the injection grade aqueous solution of the compound contains the active substance in a concentration of 10 mg/ml (1.0%).
  • the compound of this invention can be administered orally. It can be used advantageously in the form of ointment or eye lotion.
  • the oral administration may be effected more suitably in the form of tablets, capsules, powder, or suspension, for example.
  • the active component is desired to account for at least a concentration in the range of from 1.0 to 3.0% (by weight) based on the amount of the composition.
  • the daily dose of the compound is generally in the range of from 100 mg to 3,000 mg per adult.
  • Compound A and Compound B were severally dissolved in distilled water in a concentration of 5 mg/ml, to prepare master solutions.
  • Each of the master solutions was suitably diluted with an Eagle's MEM culture medium containing 10% fetal bovine serum.
  • a 0.2-ml portion of the resultant dilution product was placed on vero cells cultured in advance on a microplate and grown in a monolayer, cultured further thereon at 37°C for three to five days. Samples taken severally after three days'and five days'culture were placed under a microscope and tested for cytopathogenic effect brought about by a chemical agent.
  • cytopathogen The degree of cytopathogen was rated on the four-point scale, wherein +++ is virtually perfect extirpation of cells, ++ is strong cytopathogen observed in spite of persistence of cellular form, + is cytopathogen observed slightly and yet clearly as compared with a control (untreated sample), and - is virtually no change observed in cellular form.
  • vero cells were placed in varying ratios falling in the range of (7.8 to 0.7) x 10.4/0.9 ml and separately prepared solutions of Compound A and Compound B (prepared with an Eagle's MEM culture medium containing 10% fetal bovine serum) were added each in a volume of 0.1 ml to produce samples having final concentrations of 100, 200, and 500 ⁇ g/ml and cell numbers of (7.8 to 0.7) x 104/ml.
  • Samples of the control group contained 0.1 ml of a culture solution (an Eagle's MEM culture medium containing 10% fetal bovine serum).
  • the test was conducted by using three culture tubes per group, culturing the cells in the tubes at 37°C for three days, and taking count of live cells by the dye-exclusion method.
  • Vero cells cultured and grown in a monolayer on microplates to test for cytopathic effect due to viral infection with solutions of Compound A diluted to varying ratios and solutions of virus diluted to varying ratios added severally thereto in a volume of 0.1 ml, were cultured under the conditions of 5% CO2 and 37°C and were examined for CPE manifestation under a microscope. The observation was continued for five to six days.
  • the degree of CPE brought about by viral infection was rated on the five-point scale, wherein 3 stands for CPE observed on not less than 75% of cultured cells, 2 for CPE observed on 50% of cultured cells, 1 for CPE observed on 25% of cultured cells, 0.5 for occurrence of one to two extremely minute DPE spots, and 0 for perfect absence of recognizable CPE.
  • the CPE scores obtained at the four holes in each microplate were averaged and the difference of the average from the average obtained in the control (omitting the treatment with a chemical) was reported as ⁇ CPE.
  • TCID50 The amount of virus infecting 50% of tissues was determined by the Read-Munch method and expressed in negative logarithm of the maximum radio of dilution of virus. The difference of the amount thus determined from the amount found in the control (omitting the treatment with a chemical) was reported as ⁇ TCID50. A sample whose ⁇ CPE's found on the last day of observation and on each of the days spent for the observation exceeded 1.0 was evaluated as effective.
  • the antiviral effects, ⁇ TCID50, of the samples containing Compound A at varying concentrations of from 5 to 100 ⁇ g/ml, found on the fifth day of observation were invariably 0.3.
  • the antiviral effect, ⁇ TCID50, of the sample containing ACV in a concentration of 100 ⁇ g/ml (1/10 MNTD) was 2.5.
  • Compound A showed a relatively weak antiviral effect on the herpes simplex virus type 1 (HF strain).
  • TCID 50 The antiviral effect, of Compount A against the herpes simplex virus type 2 (169 strain) found on the fifth day of observation was 0.2 at a concentration of 10 ⁇ g/ml, 0.3 at e concentration of 20 ⁇ g/ml, 1.0 at A concentration of 50 ⁇ g/ml, and 3.0 at A concentration of 100 ⁇ g/ml.
  • ⁇ TCID 50 the antiviral effect of the known antiviral agent ACV was 3.0 at a concentration of 100 ⁇ g/ml, a value equaling that of Compound A at a concentration of 100 ⁇ g/ml.
  • Compound A showed the same degree of antiviral effect against the herpes simplex virus type 2 (169 strain) as ACV.
  • the antiviral effect, ⁇ TCID50, of Compound A on the sixth day of observation was 1.3 at a concentration of 100 ⁇ g/ml and > 2.8 at a concentration of 200 ⁇ g/ml.
  • the antiviral effect, ⁇ TCID50, of the known antiviral agent ACV was 2.0 at a concentration of 100 ⁇ g/ml.
  • neither adenine arabinoside (Ara-A) nor (IDU) showed no discernible antiviral effect at a concentration of 20 ⁇ g/ml.
  • Compound A showed a strong antiviral activity against the herpesvirus 1 type (HF strain) and effected higher control than ACV.
  • the antiviral effect, ⁇ TCID50, of Compound A on the sixth day of observation was >3.2 at a concentration of 100 ⁇ g/ml and >3.2 at a concentration of 200 ⁇ g/ml, while that of the known antiviral agent ACV was 3.2 at a concentration of 100 ⁇ g/ml, that of IDU was 1.2 at a concentration of 20 ⁇ g/ml, and that of Ara-A was nil (indiscernible) at a concentration of 20 ⁇ g/ml.
  • Compound A showed a stronger antiviral effect against the herpes simplex virus type 2 (169 strain) than ACV.
  • the antiviral effect, ⁇ TCID50, of Compound A on the fifth day of observation was 2.5 at a concentration of 100 ⁇ g/ml and 2.5 at a concentration of 200 ⁇ g/ml and that of Compound B was 2.5 at a concentration of 100 ⁇ g/ml and 2.5 at a concentration of 200 ⁇ g/ml.
  • the antiviral effect of the known antiviral agent ACV was 2.5 at a concentration of 100 ⁇ g/ml and that of IDU and that of Ara-A were invariably 0.3 at a concentration of 30 ⁇ g/ml.
  • Compound A and Compound B showed a strong antiviral activity against the herpes simplex virus type 1 (KOS strain). Their antiviral effects were equal to the antiviral activity of the known antiviral agent ACV.
  • the control ratio of Compound A was 99.7% at a concentration of 50 ⁇ g/ml, >99.9% at a concentration of 100 ⁇ g/ml, and >99.9% at a concentration of 200 ⁇ g/ml.
  • the control ratio of Compound B was 99.8% at a concentration of 50 ⁇ g/ml, >99.9% at a concentration of 100 ⁇ g/ml, and >99.9% at a concentration of 200 ⁇ g/ml.
  • control ratio of Ara-A was >99.9% at a concentration of 30 ⁇ g/ml, that of IDU 99.8% at a concentration of 30 ⁇ g/ml, and that of ACV >99.9% at a concentration of 100 ⁇ g/ml.
  • the control ratio of Compound A was 97.6% at a concentration of 50 ⁇ g/ml, 99.7% at a concentration of 100 ⁇ g/ml, and >99.9% at a concentration of 200 ⁇ g/ml, while that of Compound was 98.1% at a concentration of 50 ⁇ g/ml 99.3% at a concentration of 100 ⁇ g/ml, and 99.8% at a concentration of 200 ⁇ g/ml.
  • control ratio of Ara-A was >99.9% at a concentration of 30 ⁇ g/ml, that of IDU >99.9% at a concentration of 30 ⁇ g/ml, and that of ACV >99.9% at a concentration of 100 ⁇ g/ml.
  • heteropolyoxometalate ions of this invention manifest strong antiviral effect against herpes simplex virus type 1 (HF and KOS strains) and herpes simplex virus type 2 (169 strain). This effect is equal to or higher than the effect produced against herpesvirus by ACV, the most effective antiviral agent existing today.
  • Compound A and Compound B control not less than 99.9% of the intracellular and extracellular viruses in the one-step growth of vero cells.
  • this invention concerns an antiviral agent having as an active component thereof the salt of a heteropolyoxometalate ion represented by the general formula [XM12O40] p- .
  • the compounds of the formula exhibit a strong antiviral activity against herpes simplex virus type 1 and herpes simplex type 2. Their antiviral effects are superior to those produced by ADV, Ara-A, IDU, etc. which have been already in clinical use.
  • the compounds show very low in vitro cyto-toxicity and exhibit very low toxicity against mice. Moreover, since these compounds are readily soluble in water, they allow very easy handling and permit stable formulation of medicine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Agent antiviral contenant en tant qu'ingrédient actif un sel à ion hétéropolyacide représenté par la formule générale [XM12O40]p-1, dans laquelle X représente un ion sélectionné dans le groupe composé d'éléments des groupes III à VI du tableau périodique et de métaux de transition, M représente un élément parmi molybdène, tungstène, aluminium, vanadium, niobium, tantale, cobalt, nickel et titane, ou un mélange contenant jusqu'à trois des éléments susmentionnés, O représente oxygène et p représente un nombre entier positif.
EP19890900652 1988-12-16 1988-12-16 Antiviral agent Withdrawn EP0450065A4 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1988/001280 WO1990006756A1 (fr) 1988-12-16 1988-12-16 Agent antiviral

Publications (2)

Publication Number Publication Date
EP0450065A1 true EP0450065A1 (fr) 1991-10-09
EP0450065A4 EP0450065A4 (en) 1992-01-02

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EP19890900652 Withdrawn EP0450065A4 (en) 1988-12-16 1988-12-16 Antiviral agent

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EP (1) EP0450065A4 (fr)
WO (1) WO1990006756A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021934A1 (fr) * 1992-05-01 1993-11-11 Commonwealth Scientific And Industrial Research Organisation Heteropolytungstates utilises dans le traitement des infections a flavivirus
WO1995011033A1 (fr) * 1993-10-22 1995-04-27 Commonwealth Scientific And Industrial Research Organisation Polyoxometallates utilises dans le traitement des infections associees au flavivirus
DE102009003466A1 (de) * 2009-02-11 2010-08-19 Karlsruher Institut für Technologie Hexaalkylguanidiniumsalze

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4336642C2 (de) * 1993-10-22 1995-08-10 Deutsches Rheuma Forschungszen Verwendung von Vanadiumverbindungen mit antiviraler Wirkung
JP2004099584A (ja) 2002-05-02 2004-04-02 Keio Gijuku Ｈｓｖを用いた抗腫瘍剤
JP2005281299A (ja) * 2004-03-01 2005-10-13 Paratex Japan:Kk 抗菌・防カビ剤及びそれを用いた塗料組成物
CN116421773A (zh) * 2023-04-07 2023-07-14 广东工业大学 一种抗菌纳米簇凝胶及其制备方法与应用

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2117803B1 (fr) * 1970-12-18 1974-03-22 Anvar
FR2334366A2 (fr) * 1975-12-10 1977-07-08 Anvar Application a titre d'agents antiviraux de composes d'heteropolyanions contenant du tungstene combine a de l'antimoine
FR2372633A2 (fr) * 1976-12-03 1978-06-30 Anvar Compose d'heteropolyanions contenant du tungstene combine a de l'antimoine, leur obtention et leurs applications
FR2424028A1 (fr) * 1978-04-28 1979-11-23 Anvar Composes d'heteropolyanions contenant du tungstene combine a de l'arsenic, procede d'obtention et application a titre de medicaments antiviraux
JPH0629191B2 (ja) * 1984-09-04 1994-04-20 株式会社ポリトロニクス 抗腫瘍剤、抗ウィルス剤
IL77188A (en) * 1984-12-03 1989-03-31 Pasteur Institut Pharmaceutical compositions containing hpa23 for the treatment of acquired immune deficiency syndrome and analogous syndromes
JPS62230619A (ja) * 1986-03-31 1987-10-09 Poritoronikusu:Kk ヘテロポリ酸イオンのアルカリ塩
JPS62230620A (ja) * 1986-03-31 1987-10-09 Poritoronikusu:Kk ヘテロポリ酸イオンのアルカリ塩

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents have been disclosed. *
See also references of WO9006756A1 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021934A1 (fr) * 1992-05-01 1993-11-11 Commonwealth Scientific And Industrial Research Organisation Heteropolytungstates utilises dans le traitement des infections a flavivirus
WO1995011033A1 (fr) * 1993-10-22 1995-04-27 Commonwealth Scientific And Industrial Research Organisation Polyoxometallates utilises dans le traitement des infections associees au flavivirus
DE102009003466A1 (de) * 2009-02-11 2010-08-19 Karlsruher Institut für Technologie Hexaalkylguanidiniumsalze

Also Published As

Publication number Publication date
EP0450065A4 (en) 1992-01-02
WO1990006756A1 (fr) 1990-06-28

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